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2000
Volume 32, Issue 13
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X
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Abstract

Background and objective

Based on comprehensive network-pharmacology and molecular docking analysis, this study was intended to unveil the multiple mechanisms of Si-Ni-San (SNS) in treating anxious insomnia.

Methods

The compounds of SNS were meticulously analyzed, selected and standardized with references to their pharmacological attributes. The components included chaihu (), baishao (), zhishi () and gancao (). We used the Traditional Chinese Medicine System Pharmacology (TCMSP) Database, Traditional Chinese Medicines Integrated Database (TCMID), GeneCards database, therapeutic target database (TTD) and comparative toxicogenomic database (CTD) to construct the components-compounds-targets networks and used Cytoscape 3.9.1 software to visualize the outcome. Afterwards, the STRING database and Cytoscape 3.9.1 software were utilized to construct and visualize the protein-protein interaction (PPI) network analysis. In addition, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were also conducted through the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The molecular docking program was carried out using AutoDock 4.2 software to understand interactions between target receptors and compound ligands selected for study.

Results

We thoroughly sorted and filtered 31 pharmacologically active compounds from SNS. Subsequently, several potential target genes were predicted, of which there were 59 target genes distinctly associated with anxious insomnia. The PPI analysis indicated that the core target proteins included AKT1, IL6, TNF, SLC6A4, MAOA and GABRA2. The results of our study indicated that SNS potentially remediates anxious insomnia by reducing inflammation, neurodegeneration, and cell apoptosis of neurons. In addition, GO and KEGG enrichment analysis results indicated that SNS could modulate multiple aspects of anxious insomnia through mechanisms related to pathways of neuroactive ligand-receptor interaction. These pathways include various kinds of synaptic transmission pathways, and anti-inflammatory activity associated with response pathways. When we compared the components-compounds-targets networks and the compounds-targets-synaptic pathways networks, the five active compounds, including beta-Sitosterol, Kaempferol, Tetramethoxyluteolin, Isorhamnetin and Shinpterocarpin, were selected to conduct molecular docking experiments. Eleven target proteins, (AKT1, SLC6A4, ADRB2, MAOA, ACHE, ESR1, CYP3A4, CHRNA7, GABRA2, HTR2A and NOS3), which also play significant roles in regulating serotonergic, cholinergic, dopaminergic and GABAergic systems in the PPI network, were selected to act as receptors in molecular docking trials. The results showed that docking pairs isorhamnetin-AKT1, isorhamnetin-SLC6A4, β-sitosterol-MAOA, β-sitosterol-ACHE, isorhamnetin-CHRNA7 and shinpterocarpin-GABRA2 provided the most stable conformations of ligand-receptor binding between key compounds and core target proteins in the SNS.

Conclusion

In the study, we offer a computational result, revealing that SNS may alleviate sleep disorders associated with anxiety through a “multi-compounds, multi-targets, and multi-pathways” mechanism. The network-pharmacology and molecular docking outcomes could theoretically confirm the anti-anxiety and anti-insomnia effects of SNS. Although this research is purely statistical and systematic without empirical validation, it serves as a stepping stone and cornerstone for subsequent experimental investigations.

© 2025 The Author(s). Published by Bentham Science Publishers. 
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
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Multi-target Mechanisms of Si-Ni-San on Anxious Insomnia: An Example of Network-pharmacology and Molecular Docking Analysis
Curr. Med. Chem. 32, 2640 (2025); https://doi.org/10.2174/0109298673299665240924090617
/content/journals/cmc/10.2174/0109298673299665240924090617
/content/journals/cmc/10.2174/0109298673299665240924090617
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  • Article Type:     Research Article
Keyword(s): anxious insomnia; gene oncology; IL6; molecular docking; network pharmacology; Si-Ni-San

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